Project Summary/Abstract A wide range of evidence points to the critical role that signals from the gut, acting in the CNS, play in the regulation of food intake, body weight and the disposition of metabolic fuels including glucose. Some of the most powerful evidence for the critical nature of this ?gut-brain? axis comes from direct manipulations of the GI tract that occur during various bariatric surgical procedures. These procedures are often thought of as ?restrictive? or ?malabsorptive?, however, it is clear that the potent effects of these procedures to reduce body weight and glucose levels are the product of altering the activity of the gut-brain axis. The important point is that manipulation of the gut via these surgical interventions provides the largest and most sustained weight loss in individuals with obesity compared to any other therapeutic option. Thus a better understanding of the gut-brain axis is crucial for the development of new, less invasive and more scalable solutions to treat obesity. While the importance of the gut-brain axis is clear, our understanding of how this axis works remains incomplete. This program project grant will bring together a range of experiences and technical approaches under a single coordinated project that will allow for rapid understanding of the impact of gut, neural and hormonal signals on their crucial targets within brainstem neural circuitry. To that end, the current projects will utilize advanced neuroanatomical tracing, electrophysiology, activation and silencing of circuits, next generation sequencing and apply all of these methods exclusively in molecularly defined cell-types using a broad range of mouse models we have developed. These approaches will be combined with a range of behavioral and physiological measures of food intake, energy expenditure and GI function. Finally, we will bring to bear advanced surgical approaches that allow for assessment of the impact of bariatric surgery in these mouse models. The ultimate goal of this project is to identify key aspects of how the GI tract impacts these neuronal circuits, the identification of key neuronal populations that are the target of those GI signals and how each population can influence food intake, body weight and regulate GI function. The guiding hypothesis is that the signals generated and the neural circuit engaged by toxins and those by normal presentation of nutrients to the GI tract will be distinct in several key regions of the brainstem. The detailed understanding of these parallel circuits will allow for a better understanding of existing therapies that target the brainstem and the development of entirely new therapeutic strategies that appropriately engage this circuitry in a manner that is similar to what happens after bariatric surgery.